Human cytomegalovirus (HCMV) causes widespread, persistent human infections that vary with the age and immunocompetence of the host. It can remain latent throughout the lifetime of the host with sporadic reactivation events. The primary infection of hosts with a functional immune system is associated with mild symptoms although it may progress with fever, hepatitis, splenomegaly and a mononucleosis-like disease. In contrast, when primary infection or reactivation occurs in immunocompromised or immunodeficient hosts, they often experience life-threatening diseases, including pneumonia, hepatitis, retinitis and encephalitis (Sinclair and Sissons, J. Gen. Virol. 87:1763-1779, 2006). HCMV infection has been recognized for its association with three different populations: neonates with immature immune systems; transplant recipients with impaired immune systems due to the use of drugs and HIV-infected patients with compromised immune systems due to the decline of CD4+ T cells.
HCMV can be particularly devastating in neonates, causing defects in neurological development. In the industrialized countries, intrauterine viral infection is most common. Estimates suggest that between 0.6% and 0.7% (depending on the seroprevalence of the population examined) of all new neonates are infected in utero (Dollard et al., Rev. Med. Virol., 17(5):355-363, 2007). In the United States alone, this corresponds to approximately 40,000 new infections each year. Around 1.4% of intrauterine CMV infections occur from transmission by women with established infection. New maternal infection occurs in 0.7 to 4.1% of pregnancies and is transmitted to the fetus in about 32% of cases. Around 90% of infected infants are asymptomatic at birth and most will develop serious consequences of the infection over the course of several years, including mental retardation and hearing loss. Other infected children show symptomatic HCMV disease with symptoms of irreversible central nervous system involvement in the form of microencephaly, encephalitis, seizures, deafness, upper-motor neuron disorders and psychomotor retardation (Kenneson et al., Rev. Med. Virol., 17(4):253-276, 2007). In sum, approximately 8,000 children in the United States develop virus-related neurological disease each year. Congenital infection is the major driving force behind efforts to develop an HCMV vaccine.
CMV envelope glycoproteins gB, gH, gL, gM and gN represent attractive vaccine candidates as they are expressed on the viral surface and can elicit protective virus-neutralizing humoral immune responses.
Some CMV vaccine strategies have targeted the major surface glycoprotein B (gB), which can induce a dominant antibody response (Go and Pollard, J Infect Dis. 2008; 197:1631-1633). Glycoprotein B (gB) is a trimeric protein that is highly conserved among the different strains of HCMV, as well as among other Herpesviruses, such as Herpes Simplex Virus (HSV) and Epstein Barr Virus (EBV). It belongs to the Class III viral fusion proteins and plays a critical role in the viral replicative cycle by fusing the viral membrane with that of the target cell, facilitating delivery of the viral genome into the cytoplasm. Clinical trials are in progress to evaluate the efficacy of subunit as well as virus-like particle vaccine candidates incorporating various forms of HCMV gB. CMV glycoprotein gB can induce a neutralizing antibody response, and sera from CMV-positive patients is largely composed of antibodies directed against gB (Britt, Journal of Virology 64:1079-1085, 1990).
WO/2012/049317 discloses CMV gB polypeptide comprising a fusion loop 1 (FL1) domain and a fusion loop 2 (FL2) domain, wherein at least one of the FL1 and FL2 domains comprises at least one amino acid deletion or substitution. Examples show that the percentage of gB trimers was around 70%.
A need exists for an effective vaccine that is targeted to the CMV glycoprotein gB and for immunization methods that produce better immune responses.